Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.

中文翻译：

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跨77,184个外显子组的单基因代谢条件下外显力和可变表达的决定因素

据报道，成千上万的遗传变异会导致严重的单基因疾病，但是对于几乎所有变异基因来说，变异携带者会发展这种疾病的可能性（称为外显率）都是未知的。此外，常见的多基因变异的临床应用仍不确定。使用来自77,184名成年个体（来自2型糖尿病病例对照研究的38,618名多祖先个体和来自UK Biobank的38,566名参与者的外显子组测序，他们也可获得基因型阵列数据），我们应用了临床护理标准基因变异八个单基因代谢疾病的治疗。导致单基因糖尿病和血脂异常的罕见变体显示出的效应大小明显大于相应多基因得分的前1％。不过，在两项研究中，除单基因糖尿病外，所有条件下单基因变异携带者的外显率估计平均低于60％。我们评估了有助于预测风险的其他流行病学和遗传因素，证明包括常见的多基因变异显着改善了两种单基因血脂异常的生物标志物估计。